2-Substituted benzodioxoles

ABSTRACT

2-Substituted benzodioxoles are useful as pharmaceuticals having e.g. anti-inflammatory, analgesic, antipyrretic, antitussive, C.N.S. depressant, local anaesthetic, antiarrythmic, antihistaminic action and hypolipidic action.

The present invention provides, as new compounds, the benzodioxoles ofthe formula: ##SPC1##

In which R represents hydrogen, lower alkyl, lower haloalkyl lowerhydroxy-alkyl or an aryl or aralkyl residue unsubstituted or substitutedby, in the aromatic ring, halogen or alkyl, or by hydroxyl or alkoxy;alk represents a lower, straight, branched, or cyclic, saturated orunsaturated alkyl group; and R and alk can be joined to form a spiranenucleus; R¹ represents hydrogen, halogen, lower alkyl, lower haloalkyl,hydroxy, nitro, amino, substituted amino, or a benzene ring condensed onthe benzodioxole nucleus; and R² represents (a) a group --O--R³ in whichR³ hydrogen, straight or branched alkyl, hydroxy-alkyl, aralkyl,aminoalkyl, or aminohydroxyalkyl; in which the amino group isunsubstituted or mono or disubstituted by lower alkyl or may form partof a heterocyclic ring (e.g. morpholine, pyrrolidine and the like); or(b) a group of formula: ##EQU1## in which R⁴ and R⁵, which can be thesame or different each represent hydrogen, (linear, branched, orcyclic), lower alkyl hydroxyalkyl or aralkyl, aminoalkyl, in which theatom of nitrogen is unsubstituted, monosubstituted or disubstituted byalkyl or may form part of a heterocyclic ring, hydroxy, an acid group,or aryl unsubstituted or substituted by alkyl or halogen; or the group##EQU2## represents the residue of an heterocyclic amine (e.g.pyrrolidine, morpholine, piperidine, piperazine, or N-substitutedpiperazine provided that when R = CH₃ and R¹ = H or 5--CH₃, the grouping--alk--CO--R² is different from carboxymethyl, 2-carboxyethyl,1-methyl-2-carboxyethyl, 2-carboxypropyl, and the respective ethylesters; when R = CH₃ and R¹ = 5--NO₂, the said grouping is differentfrom carboxymethyl and the respective ethyl ester; when R = phenyl andR¹ = H, the said grouping is different from carboxymethyl andcarbomethoxymethyl; and when R = H and R¹ = H the said grouping isdifferent from --CH₂ --CONH₂.

According to the invention, the aforesaid compounds are obtained byreaction between the appropriately substituted pyrocatechol and theirester derivatives with the carbonic or sulphuric acids and a ketoneester, a ketone amide or a ketone nitrile having the carbonyl functionin beta, gamma and delta positions in relation to the other group in alinear branched or cyclic chain. Instead of the carbonyl compounds, thecorresponding derivatives can be used, such as acetals with aliphaticalcohols, gem-dichloro- or di-bromo- compounds, enolic forms, orenamines.

As a condensing reagent, phosphoric anhydride is preferably used butother reagents can also be used, e.g. sulphuric, phosphoric,polyphosphoric, hydrochloric or trifluoroacetic acids, pyridinehydrochloride, calcium chloride, paratoluenesulphonic acid, ion exchangeresins (such as Amberlite IRA 120), dicyclohexylcarbodiimide; ormolecular sieve. The reaction temperature can vary between 0°-150°C. andthe reaction is effected in the presence of at least one inert organicsolvent, e.g. an aliphatic or aromatic hydrocarbon, a halogenoderivative thereof, an ether, ester or amide.

According to a variant of the process, the substituted pyrocatechol, orone of its reactive derivatives, is reacted with a dibromoester or adibromoamide of the formula: ##EQU3## in which R and R² have theaforementined meanings, or with the corresponding nitrile.

In place of the dibromo derivative, a bromoolefine of the formula:##EQU4## can also be used, especially where "n" = 0.

Preferably, the reaction is carried out in dimethylformamide in thepresence of sodium hydroxide, at room temperature, but thedimethylformamide can be replaced by other solvents like the onesalready described (and in addition, by ketones, such asmethylethylketone and the like), and the sodium hydroxide by other basiccatalysts, either organic or inorganic. If sodium methoxide is used,there forms together with the benzodioxole, also the benzodioxaneisomer, which can be separated with suitable manipulation.

The benzodioxole ring can be obtained, according to another variant, byreaction of a pyrocatechol with an acetylene derivative of the formula:

    R--C C--(CH.sub.2).sub.n --COR.sup.2

in an anhydrous solvent belonging to the beforementioned classes, inpresence of an organic or inorganic basic catalyst (e.g. tributylamineor potassium carbonate) at a temperature ranging from 0° to 100°C.

In the cyclization reaction intermediate compounds of the followingformula can also be isolated: ##SPC2##

which, after being treated with alkaline agents (e.g. potassiumcarbonate) cyclize easily to give the corresponding benzodioxole.

In the cyclisation products obtained with the above methods, the residueR² can obviously be transformed by the common methods of organicchemistry, so as to have the other means ascribed to same in the generalformula I.

One can thus obtain the acids (R² = OH) from the corresponding esters,amides and nitriles by acid or basic saponification; vice-versa, one cantransform the acids into corresponding esters by using the commonesterification methods which consist, for instance, in making the acid(or one of its metallic salts or a reactive derivative like anotherester, a chloride, or a mixed anhydride reacting with an alcohol R³ --OH(in which R³ has the beforementioned meaning) or with a relativederivative of the latter (e.g. an ester with a hydrohalic acid orp-toluenesulphonic acid) in the presence of at least one of the suitablecatalysts which, according to the reaction, may be preferably an acid(e.g. hydrochloric acid, sulphuric acid, p-toluenesulphonic acid, or aLewis-acid) or a base (where transesterifications are involved e.g. analkali metal alkoxide, sodium hydroxide, or sodamide). Similarly, thebenzodioxole acid (or one of its beforementioned reactive derivatives)can be converted into a corresponding amide by reaction with an amine offormula: ##EQU5## in which R⁴ and R⁵ have the meanings which have dulybeen described. In addition, there is a conversion of an acid into itshigher homologues by Arndt-Eistert reaction, as in the case of formationof an acid by Grignard reaction between a halogen derivative of theformula ##SPC3##

with magnesium and carbon dioxide.

The compounds of the general formula which contain one or moreasymmetric atoms of carbon can be split into their stereoisomers byusing the common separation methods.

From the compounds of the general formula 1, which contain a basicgroup, salts can be obtained with pharmaceutically acceptable inorganicacids, e.g. hydrochloric acid, hydrazoic acid, nitric acid, sulphuricacid, or phosphoric acid, and organic carboxylic acids, for instancepropionic acid, glycolic acid, maleic acid, succinic acid, hydroxymaleicacid, fumaric acid, malic acid, tartaric acid, citric acid, glucuronicacid, benzoic acid, mandelic acid, salicylic acid, 4-aminosalicyclicacid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, pamoic acid,nicotinic acid, and isonicotinic acid, and organic sulphonic acids, e.g.methanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonicaci acid, ethane-1,2-disulphonic acid, p-toluenesulphonic acid, ornaphthalene-2-sulphonic acid. Mono and poly salts are formed accordingto the number of salt-forming groups present in the molecules.Similarly, from the compounds of the formula 1, which contain an acidgroup, pharmaceutically acceptable salts can be obtained with metals(such as sodium, potassium, calcium, magnesium, and aluminium) or withorganic bases (such as morpholine, pyrrolidine, ethanolamine, andN,N-dibenzylethylenediamine).

The benzodioxole derivatives of the invention have interestingpharmacological properties and, according to the substituents present,have anti-inflammatory, analgesic, antipyrretic, antitussive, C.N.S.depressant, local anaesthetic, antiarrythmic and antihistaminic action.Some of the compounds also have a hypolipidic action.

The new compounds can be administered topically, orally, or by injectionas suitable pharmaceutical formulations in solid, liquid and suspensionform e.g. as ointments, lotions, tablets, capsules, phials or syrups.

The tables that follow summarise the pharmacological characteristics ofspecific compounds described in this application, which are denoted bythe following numbers:

LR 272 : (2-phenyl-1,3-benzodioxol-2-yl)acetic acid

LR 273 : (2-methyl-1 1,3-benzodioxol-2-yl)acetic acid

LR 289 :N-(N',N'-diethylaminoethyl)-2-(2-phenyl-1,3-benzodioxol-2-yl)acetamidehydrochloride.

LR 290 :N-(N',N'-diethylaminoethyl)-2-(2-methyl-1,3-benzodioxol-2-yl)acetamidecitrate.

LR 292 : N,N-diethylaminoethyl(2-methyl-1,3-benzodioxol-2-yl)acetatecitrate.

LR 293 :N,N-diethylaminoethoxyethyl-(2-methyl-1,3-benzodioxol-2-yl)acetatecitrate.

LR 295 : N-morpholinoethyl-(2-phenyl-1,3-benzodioxol-2-yl)-acetatemaleate.

LR 296 : N-morpholinoethyl-(2-methyl-1,3-benzodioxol-2-yl)-acetate.

LR 310 : (2-phenyl-1,3-benzodioxol-2-yl)acetamide.

LR 347 : N-(tert-butyl)-2-(2-phenyl-1,3-benzodioxol-2-yl)-acetamide.

LR 356 : N,N-dimethyl-2-(2-phenyl-1,3-benzodioxol-2-yl)-acetamide.

LR 411 : Ethyl(2-phenyl-5-chloro-1,3-benzodioxol-2-yl)-acetate.

LR 444 : (2-phenyl-1,3-benzodioxol-2-yl)aceto-hydroxamic acid.

LR 445 :N-(N',N'-diethylaminoethyl)-spiro-[1,3-benzodioxol-2,1'-cyclohexane]-2'-carboxyamidecitrate.

LR 449 : N-benzyl-2-(2-methyl-1,3-benzodioxol-2-yl)-acetamide.

LR 471 :N-(N',N'-diethylaminoethyl)-3-(2-methyl-1,3-benzodioxol-2-yl)-propionamide.

LR 492 :N-(N',N'-diethylaminoethyl)-2-(2-methyl-1,3-benzodioxol-2-yl)-propionamidecitrate.

LR 493 :N-(N',N'-diethylaminoethyl)-2-(2,5-dimethyl-1,3-benzodioxol-2-yl)-acetamidecitrate.

The tables also show data for some drugs for comparison(phenyl-butazone, dihydrocodeinone, quinidine).

    __________________________________________________________________________                    Anti-inflammatory                                                             activity in the rat  Analgesic activity                                       (carraghenin oedema) dose                                                                          (acetic acid-induced                              LD.sub.50 rat                                                                        reducing inflammation                                                                       Therapeutic                                                                          stretching) % of rats                    Compound mg/Kg. e.p.                                                                          by 15%-mg/kg.e.p.                                                                           Index  protected                                __________________________________________________________________________    LR 411                                                                                 >1000  200           >5     32                                                LR 290   490         50     9.8         φ                                 LR 292   1000        150    6.7         φ                                 LR 347 >1000         150    >6.7        30                                    LR 356 >1000         200    >5.0        50                                    LR 449   1000        200    5.0         30                                    LR 471   150         50     3.0         20                                    LR 444   150         50     3.0         20                                    Phenylbutazone                                                                         450         50     9.0         40                           __________________________________________________________________________

    __________________________________________________________________________                     Anti-tussive activity                                                         in the rate (NH.sub.3                                                  LD.sub.50 rat                                                                        aerosol) ED.sub.50                                                                        Therapeutic index                                Compond   mg/kg. e.p.                                                                          mg./kg. e.p.                                                                              LD.sub.50 /ED.sub.50                             __________________________________________________________________________    LR 272    250    33          7.6                                              LR 273    250    15          15.7                                             LR 293    720    67          10.7                                             LR 296    >1000  86          >11.6                                            LR 289     90    14          6.4                                              LR 310    940    88          10.7                                             LR 347    >1000  115         >8.7                                             LR 295    490    64          7.7                                              Dihydrocodeinone                                                                        100    4.0         25.0                                             __________________________________________________________________________

    __________________________________________________________________________                 Anti-arrythmic                                                                activity in the                                                               rat (CaCl.sub.2 arrythmia)                                                                        Local anaesthetic                                  LD.sub.50 rat                                                                        ED.sub.50 mg./kg.                                                                          Therapeutic                                                                          activity in rats                             Compound                                                                            mg./Kg. e.p.                                                                         e.v.         Index  total ED.sub.50 mg. i.d.                     __________________________________________________________________________    LR 293                                                                              720    1.7          423.5  0.35                                         LR 292                                                                              >1000  3.5          >285.7 φ                                        LR 290                                                                              490    3.6          136    φ                                        LR 445                                                                              150    3.2          46.9   φ                                        LR 492                                                                              250    6.3          39.7   φ                                        LR 493                                                                              250    8            31.3   φ                                        Quinidine                                                                           150    4.8          31.3   0.9                                          __________________________________________________________________________

The following Examples illustrate the invention. The melting and boilingpoints are not corrected. The identity of the substances and theirpurity are determined by elementary analyses of C, H and N (and thehalogens when present), infra-red spectra, N.M.R. and U.V.

The products mentioned in this invention have not yet been described inliterature, with the exception of:

a. 3-(2-methyl-1,3-benzodioxol-2-yl)propionic acid and the correspondingethylester; 2-methyl-2-(2-methyl-1,3-benzodioxol-2-yl) propionic acidand the corresponding ethylester. (R.T. Arnold et al, J.A.C.S. 54, 1410(1942);

b. (2-phenyl-1,3-benzodioxol-2-yl)acetonitrile;(1,3-benzodioxol-2-yl)acetonitrile; (1,3-benzodioxol-2-yl)-acetamide. V.Rosnati, Sannicolo, G. Pagani, Gazz. Chimm. Ital 98 1069 (1968).

For none of these compounds has any pharmacological activity beenmentioned.

EXAMPLE 1

Ethyl(2-p-chlorophenyl-1,3-benzodioxol-2-yl)-acetate.

98.9 g of P₂ O₅ is added to a mixture of 64 g of ethylp-chlorobenzoylacetate and 90.4 g of pyrocatechol, heated at 80°C inportions over about 1/2 hour. After 15 minutes the heating isinterrupted and 1000 cc of benzene are added. The organic phase isdecanted. The latter is repeatedly washed first with NaHCO₃ andsubsequently with H₂ O until same is rendered neutral and finally driedwith Na₂ SO₄. The solvent is removed in vacuum and the residual oilfractionated, b.p. 150°-155°C (0.4 mm.Hg).

Similarly, one prepares:

ethyl (2-phenyl-1,3-benzodioxol-2-yl)acetate(b.p. 173°-176°C/l mm).

ethyl(2-bromomethyl-1,3-benzodioxol-2-yl)acetate (b.p. 146°-150°C/0.4mm).

ethyl spiro-(1,3-benzodioxol-2,1'-cyclohexane)-2'-acetate (b.p.120°-124° C/0.3 mm).

ethyl(2-ethyl-1,3-benzodioxol-2-yl)acetate (b.p. 91°-92°C/0.4 mm).

ethyl 3-(2-p-chlorophenyl-1,3-benzodioxol-2-yl)-propionate (b.p.200°-210°C/0.4 mm).

ethyl(2-methyl-4-methoxy-1,3-benzodioxol-2-yl)acetate (b.p.95°-100°C/0.6 mm), starting from 3-methoxypyrocatechol and ethylaceto-acetate.

ethyl(2-methyl-5-chloro-1,3-benzodioxol-2-yl)acetate (b.p.130°-140°C/1.8 mm), starting from 4-chloropyrocatechol and ethylaceto-acetate.

ethyl(2-methyl-1,3-naphthodioxol-2-yl)acetate (m.p. 61°-62°C frombenzene-hexane) starting from 2,3-dihydroxynapththalene and ethylaceto-acetate.

EXAMPLE 2

Ethyl(2-phenyl-1,3-benzodioxol-2-yl)acetate.

To a suspension of 15 g NaH (as a 50% suspension in mineral oil) in 200cc of DMF 17.1 g of pyrocatechol in 90 cc of DMF is added withrefrigeration. After 1/2h, a solution of ethyl dibromocinnamate (52.6 gin 90 cc of DMF) or of ethyl betabromocinnamate (40 g in 70 cc of DMF)is introduced with vigorous shaking and maintaining the temperaturebelow 30°C. The mixture is kept for 12 hours to allow the reaction tocomplete. The solvent is removed under reduced pressure. The residue istaken up with water and extracted with ether. The separated organicphase is repeatedly washed with 10% NaOH and subsequently with H₂ Ountil neutral. It is dried over Na₂ SO₄, and the dried product isevaporated and the residual oil fractionated. b.p. 173°-176°C/1 mm.

When sodium methoxide is used as a condensing medium,2-carbethoxy-3-phenyl-1,4-benzodioxane (b.p. 160°-165° C/0.4 mm) isobtained as a by-product.

EXAMPLE 3

Ethyl(2-methyl-1,3-benzodioxol-2-yl)acetate.

A mixture of 22.2 g of ethyl 3-methyl- 3-(o-hydroxyphenoxy) acrylate,13.8 g of K₂ CO₃ and 100 cc of anhydrous acetone is heated for 5 h.After it has been cooled, it is filtered and the solvent is eliminatedunder reduced pressure. The residue is treated as indicated in Example2. The product is an oil b.p. 83°-86°C/0.3 mm.

EXAMPLE 4

Ethyl(2-phenyl-5-chloro-1,3-benzodioxol-2-yl)acetate.

78.5 g of anhydrous K₂ CO₃ are added, in parts, to a solution of 40.5 gof ethyl phenylpropiolate and 43.5 g of chloropyrocatechol in 200 cc ofanhydrous acetone. The mixture is heated for 15 h. It is subsequentlyfiltered and the solvent eliminated at low pressure. The residue istreated as indicated in Example 2. The product has b.p. 150°-155°C/0.3mm.

EXAMPLE 5

Ethyl(2-methyl-1,3-benzodioxol-2-yl)acetate.

13 g of ethyl acetoacetate and 13.6 g of pyrocatechol carbonate areheated until evolution of CO₂ ceases. The residue is distilled underreduced pressure, b.p. 83°-86°C/0.3 mm.

EXAMPLE 6

(2-phenyl-5-chloro-1,3-benzodioxol-2-yl) acetic acid.

A mixture of 32 g. ofethyl(2-phenyl-5-chloro-1,3-benzodioxol-2-yl)acetate, 200 cc. of 95%ethanol and 150 cc. of 4% NaOH is refluxed for 2 hours. The alcohol isthen removed under vacuum and, after cooling, the mixture is acidifiedwith dilute HCl. The precipitated solid is filtered off andrecrystallised from benzene-hexane, m.p. 117°-119°C.

Similarly can be prepared:

(2-methyl-1,3-naphthodioxol-2-yl) acetic acid (m.p. 127°-128°C. frombenzene).

3-(2-p-chlorophenyl-1,3-benzodioxol-2-yl) propionic acid (m.p. 100°-1°C.from benzene-hexane).

(2-methyl-1,3-benzodioxol-2-yl) acetic acid (m.p. 60°-61°C. frombenzene).

(2-p-chlorophenyl-1,3-benzodioxol-2-yl) acetic acid (m.p. 162°-163°C.from benzene).

Spiro-(1,3-benzodioxol-2,1'-cyclohexane) acetic acid (m.p. 138°C. frombenzene.

Spiro-(1,3-benzodioxol-2,1'-cyclohexane)-2'carboxylic acid (m.p.92°-94°C. from hexane).

EXAMPLE 7

β-N-morpholinoethyl 2-(phenyl-1,3-benzodioxol-2-yl)acetate.

17.5 g of triethylamine is added to 44.7 g. of(2-phenyl-1,3-benzodioxol-2-yl) acetic acid, suspended in 200 cc. ofCHCl₃. The mixture is cooled with ice and 19 g. of ethyl chlorocarbonateare added dropwise. After 15 minutes 22.9 g. N-β-hydroxyethylmorpholineare introduced in the mixture. After 2 hours, water is added, and theorganic phase is separated and dried with Na₂ SO₄.

The solvent is removed under vacuum, and the maleate is then obtainedfrom the residual oil, m.p. 114°-115°C. (from isopropyl alcohol).

Similarly, the following can be prepared:

β-N-morpholinoethyl(2-methyl-1,3-benzodioxol-2-yl)acetate (oxalate, m.p.141°-142°C. from isopropyl alcohol).

N-benzyl-2-(2-methyl-1,3-benzodioxol-2-yl)acetamide (m.p. 105°-106°C.from benzene).

N-benzyl-2-(2-phenyl-1,3-benzodioxol-2-yl)-acetamide (m.p. 102°-103°C.from benzene-hexane).

N-(N',N'-Diethylaminoethyl)-2-(2-methyl-5-nitro-1,3-benzodioxol-2-yl)acetamide(b.p. 230°-245°C./0.4 mm).

EXAMPLE 8

N,N-Diethylaminoethyl(2-methyl-1,3-benzodioxol-2-yl)-acetate.

To a suspension of 19.4 g. of (2-methyl-1,3-benzodioxol-2-yl)acetic acidin 100 cc. of anhydrous acetone, 10.6 g. of Na₂ CO₃ and subsequently13.5 g. of N,N-diethylaminoethyl chloride in 20 cc. of anhydrous acetoneare added in portions. The mixture is refluxed for 4 hours. The sodium116°-formed is filtered off and the solution is evaporated. The residualoil is converted into the citrate, m.p. 116°117°C. (from isopropylalcohol).

The following can be similarly obtained:

N,N-Diethylaminoethyl(2-phenyl-1,3-benzodioxol-2-yl)-acetate (maleate,m.p. 119°-121°C., from isopropyl alcohol).

EXAMPLE 9

N,N-Diethylaminoethoxyethyl(2-phenyl-1,3-benzodioxol-2-yl)-acetate.

To a mixture of 14.2 g. of ethyl(2-phenyl-1,3-benzodioxol-2-yl)-acetate,8.05 g. of 2-methylaminoethoxyethanol and 215 cc. of anhydrous heptane,heated to 100°C., is added in small portions a solution of sodiumethoxide (obtained from 0.165 g. of metallic sodium in 10 cc. ofabsolute ethanol). Heating is continued until the azeotropicethanol-heptane mixture no longer distils. The product is subsequentlyevaporated, and the residue is taken up with water and extracted withether. The organic phase is washed with water and dried with Na₂ SO₄.The solvent is removed under vacuum and the citrate is prepared from theresidual oil, m.p. 83°-84°C. (from isopropyl alcohol).

Similarly are prepared:

N,N-diethylaminoethoxyethyl(2-methyl-1,3-benzodioxol-2-yl)-acetate(citrate, m.p. 83°-84°C., from isopropyl alcohol);Morpholinoethoxyethyl(2-methyl-1,3-benzodioxol-2-yl)-acetate (oxalate,m.p. 108°-109°C. from isopropyl alcohol);

Morpholinoethoxyethyl(2-phenyl-1,3-benzodioxol-2-yl)-acetate (oxalate,m.p. 149°-150°C. from 95% alcohol).

EXAMPLE 10

N-(N',N'-Diethylaminoethy)-2-(2-methyl-1,3-benzodioxol-2-yl)-acetamide.

30 g. of methyl(2-methyl-1,3-benzodioxol-2-yl)-acetate are added to 52g. of N,N-diethylethylenediamine mixed with 50 mg. of metallic sodium.The mixture is heated under nitrogen until methanol released by thereaction no longer distils (4 hours). The excess amine is removed undervacuum, and the residue is converted into the citrate, m.p. 127°-128°C.(from 95% alcohol).

The following can be similarly prepared:

N-(N',N'-diethylaminoethyl)-2-(2-phenyl-1,3-benzodioxol-2-yl)-acetamide(hydrochloride, m.p. 143°-144°C. from anhydrous alcohol);

N-(N',N'-diethylaminoethyl)spiro-(1,3-benzodioxol-2,1'-cyclohexane)-2'-carboxyamide(citate, m.p. 149°-151°C. from 95% alcohol);

N-(N',N'-dimethylaminoethyl)-2-(2-methyl-1,3-benzodioxol-2-yl)-acetamide;

N-methyl-N'-(2-methyl-1,3-benzodioxol-2-yl-acetyl)-piperazine;

N-(N',N'-diethylaminoethyl)-3-(2-methyl-1,3-benzodioxol-2-yl)-propionamide(m.p. 42°-43°C.);

N-(N',N'-diethylaminoethyl)-2-(2,5-dimethyl-1,3-benzodioxol-2-yl)-acetamide(citrate, m.p. 124°-6°C. from isopropyl alcohol);

N-(N',N'-diethylaminoethyl)-2-(2-methyl-5-chloro-1,3-benzodioxol-2-yl)-acetamide;

N-(N',N'-diethylaminoethyl)-2-(2-methyl-4-methoxy-1,3-benzodioxol-2-yl)-acetamide;

N-(N',N'-diethylaminoethyl)-2-(2-methyl-1,3-benzodioxol-2-yl)-propionamide (citrate, m.p. 108°-110°C. from anhydrous alcohol).

EXAMPLE 11

(2-phenyl-1,3-benzodioxol-2-yl)-acetamide.

To 22 g. of (2-phenyl-1,3-benzodioxol-2-yl)-acetic acid in 300 cc. ofanhydrous benzene, in the cold, 18.1 g. of PCl₅ are added. After leavingthe mixture for 2 hours to allow the reaction to be completed a coldsolution of NH₃ in anhydrous ether is added to the mixture, in drops andwith shaking. After 12 hours, the mixture is poured onto ice. Theorganic phase is separated, washed with H₂ O until neutral, and finallydried with Na₂ SO₄. The solvent is removed under vacuum and the residueis recrystallised from benzene, m.p. 114°-15°C.

The following can be prepared similarly:

N,N-Dimethyl-2-(2-phenyl-1,3-benzodioxol-2-yl)-acetamide (m.p.151°-162°C. from benzene);

N-(tert-butyl)-2-(2-phenyl-1,3-benzodioxol-2-yl)-acetamide (m.p.142°-144°C. from 80% alcohol);

(2-methyl-1,3-benzodioxol-2-yl)-acetamide (m.p. 114°-6°C. frombenzene-hexane);

N,N-diethyl-2-(2-methyl-1,3-benzodioxol-2-yl)acetamide;

N-isopropyl-2-(2-methyl-1,3-benzodioxol-2-yl)acetamide;

3-(2-methyl-1,3-benzodioxol-2-yl)propionamide (m.p. 63°-4°C. frombenzene-hexane).

EXAMPLE 12

(2-Methyl-1,3-benzodioxol-2-yl)acetohydroxamic acid.

To a solution of 2.5 g. of sodium in 75 cc. of absolute CH₃ OH asolution of 3.5 g. of NH₂ OH.HCl in 50 cc. of CH₃ OH is added, and,after filtration, 11 g. of ethyl 2-methyl-1,3-benzodioxol-2-yl-acetateare added to this mixture. The mixture is refluxed for 30 minutes; themethanol is removed, and the mixture is cooled and acidified with diluteHCl. The acidified mixture is extracted with ether, and the ether phaseis separated, washed with H₂ O until it becomes neutral, and dried withNa₂ SO₄. The product obtained after evaporation of the ether has m.p120°-122°C. (from ethyl acetate).

(2-Phenyl-1,3-benzodioxol-2-yl)acetohydroxamic acid (m.p. 120°-21°C.from ethyl acetate can be similarly prepared).

EXAMPLE 13

(2-Phenyl-1,3-benzodioxol-2-yl)acetic acid.

a. (2-Phenyl-1,3-benzodioxol-2-yl)acetonitrile;

2.45 g. of catecholphosphotrichloride and 2.55 g. of(2-phenyl-1,3-benzodioxol-2-yl)-acetamide are carefully mixed in adistilling flask. The mixture is heated at 100°C., for 1 h. The mixtureis then diluted with ether and poured onto ice. The ether phase, afterbeing separated, is washed with NaHCO₃ and with H₂ O until it becomesneutral, and subsequently evaporated to dryness. The product melts at111°-112°C. (from 80% alcohol).

The same product can also be obtained by treating the correspondingacetamide with P₂ O₅.

b. 24 g. of (2-phenyl-1,3-benzodioxol-2-yl)-acetonitrile are mixed in100 cc. of 95% ethyl alcohol. To the mixture a solution of 6.85 g. of90% OH in 50 cc. of H₂ O is added. The mixture is then refluxed untilevolution of NH₃ ceases (4 h.). The alcohol is removed under vacuum andthe product is acidified by addition of dilute H₂ SO₄. The productobtained melts at 152°-153°C. (from benzene).

EXAMPLE 14

(2-Phenyl-1,3-benzodioxol-2-yl)acetic acid.

a. 2-Phenyl-2-bromomethyl-1,3-benzodioxole. To a mixture of 40 g. ofbromoacetophenone and 24 g. of pyrocatechol, heated to 90°C., 40 g. ofP₂ O₅ are added in portions. After 15 minutes, the heating isinterrupted and benzene (400 cc.) is added to the mixture. The organicphase is separated, and repeatedly washed with NaHCO₃ and with H₂ Ountil neutral, and finally dried with Na₂ SO₄. The dried extract isfractionated, and the desired product boils at 120°-125°C./0.4 mm.

b. To a mixture of 0.61 g. of magnesium, in chips, 10 cc. of anhydrousether and one crystal of iodine, one cc. of a solution of 7.3 g. of2-phenyl-2-bromoethyl-1,3-benzodioxole in 25 cc. of anhydrous ether isadded. When the reaction has begun, the mixture is stirred and the restof the mixture is then added dropwise. The mixture is then refluxed for2 hours. After cooling CO₂ is bubbled into the reaction mixture for 2hours. The mixture is then cooled with ice and hydrolysed with 25% H₂SO₄. The ether phase is then separated and dried with Na₂ SO₄. Afterevaporation, the product obtained has the m.p. 152°-53°C. (frombenzene).

EXAMPLE 15

Ethyl-3-(2-phenyl-5-chloro-1,3-benzodioxol-2-yl)-propionate.

11.7 g. of (2-phenyl-5-chloro-1,3-benzodioxol-2-yl)-acetic acid mixedwith 50 cc. of anhydrous benzene are refluxed with 10 cc. of SOCl₂ for 3hours. The solvent and the excess of SOCl₂ are removed under vacuum. Theresidual oil mixed with 150 cc. of anhydrous ether is added in drops toan ether solution of diazomethane, which is ice cooled to maintain thetemperature under 2°-3°C. After 24 h, the ether is removed under vacuumand the residue is mixed with 100 cc. of ethanol. The mixture is heatedat 50°C., and 2 g. of Ag₂ O are added. After 2 hours, the product istreated with animal charcoal, filtered and dried. It is thenfractionated and the desired product boils at 200°-207°C./0.4 mm.

EXAMPLE 16

Ethyl spiro-(1,3-benzodioxol-2,1'-cyclopentane)-2'-carboxylate.

A mixture of 15.7 g. of ethyl cyclopentanone-2-carboxylate, 11 g. ofpyrocatechol, 0.5 g. of p-toluenesulphochloride and 0.5g. ofp-toluenesulphonic acid in 100 cc. of anhydrous benzene is refluxeduntil the theoretical amount of water no longer distils azeotropically.The mixture is washed first with dilute NaOH and then with H₂ O untilneutral. After drying with Na₂ SO₄ the solvent is removed under vacuum.The residual oil is fractionated, and the desired product boils at136°-139°C./0.3 mm.

The following is prepared similarly:

Ethyl spiro-(1,3-benzodioxol-2,1'-cyclohexane)-2'-carboxylate (b.p.137°C./0.2 mm.).

EXAMPLE 17

Ethyl(2-methyl-5-amino-1,3-benzodioxol-2-yl)acetate 16 g. ofethyl(2-methyl-5-nitro-1,3-benzodioxol-2-yl)-acetate (prepared accordingto G. Sloof, Rec. Trav. Chim. 547, 995 (1935)) dissolved in 300 cc. of95% alcohol are hydrogenated at room temperature and 2 atm. of hydrogenpressure in the presence of 6 g. of Raney nickel. After the theoreticalabsorption of hydrogen, the mixture is filtered and evaporated todryness. The residual oil is purified by distillation, (b.p.190°-200°C./0.4 mm.).

The following can be prepared similarly:

(2-methyl-5-amino-1,3-benzodioxol-2-yl)acetic acid.

EXAMPLE 18

Ethyl(2-methyl-5-N,N-diethylsulphonamido-1,3-benzodioxol-2-yl)acetate.

a. To 5 g. of ethyl(2-methyl-1,3-benzodioxol-2-yl)-acetate in 25 cc. ofdried chloroform, 25 cc. of chlorosulphonic acid is added at 0°C., indrops, and with stirring. After the addition, the mixture is stirred for2 hours and then poured onto ice and extracted with ether. The organicphase, after being washed first with a solution of Na₂ CO₃ and then withH₂ O until neutral, is dried with Na₂ SO₄. The residual oil,ethyl(2-methyl-5-chlorosulphonyl-1,3-benzodioxol-2-yl)-acetate, is usedwithout further purification for the subsequent reaction.

b. To 5 g. ofethyl(2-methyl-5-chlorosulphonyl-1,3-benzodioxol-2-yl)-acetate dilutedin 50 cc. of anhydrous benzene, 2.3 g. of diethylamine are added. Themixture is refluxed for 30 minutes, and then filtered and dried. It ispurified by distillation, and the desired product boils at250°-60°C./0.4 mm.

Ethyl(2-methyl-5-sulphonamido-1,3-benzodioxol-2-yl)acetate is similarlyprepared.

EXAMPLE 19

Ethyl(2-methyl-5-acetylamino-1,3-benzodioxol-2-yl)acetate.

A mixture of 4.5 g. ofethyl(2-methyl-5-amino-1,3-benzodioxol-2-yl)-acetate and 30 cc. ofacetic anhydride is heated for 15 minutes at 100°C. After cooling, it ispoured onto ice, and allowed to stand for 2 hours. The precipitatedsolid is filtered off, and crystallised from aqueous alcohol, m.p.81°-82°C.

We claim: 1.N-((.beta.-N',N'-diethylamino)ethyl)-2-(2-methyl-1,3-benzodioxol-2-yl)-acetamideor a pharmaceutically acceptable salt thereof. 2.N-((β-N',N'-diethylamino)ethyl)-2-(2-phenyl-1,3-benzodioxol-2-yl)-acetamideor a pharmaceutically acceptable salt thereof. 3.N-((.beta.-N',N'-diethylamino)ethyl)-spiro-(1,3-benzodioxol-2,1'-cyclohexane)-2'carboxyamideor a pharmaceutically acceptable salt thereof. 4.N-((β-N',N'-dimethylamino)ethyl)-2-(2-methyl-1,3-benzodioxol-2-yl)-acetamideor a pharmaceutically acceptable salt thereof. 5.N-((β-N',N'-diethylamino)ethyl)-2-(2-methyl-1,3-benzodioxol-2-yl)-propionamideor a pharmaceutically acceptable salt thereof. 6.N-((β-N',N'-diethylamino)ethyl)-3-(2-methyl-1,3-benzodioxol-2-yl)-propionamideor a pharmaceutically acceptable salt thereof. 7.N-((β-N',N'-diethylamino)ethyl)-2-(2,5-dimethyl-1,3-benzodioxol-2-yl)-acetamideor a pharmaceutically acceptable salt thereof.